Stress sensitization during the juvenile period in rodents: Impact of neurotrophins and behavioral flexibility

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Stressors may engender the `sensitization' of neurobiological processes (e.g., neurotransmitter, hormone and growth factors) so that later responses to stressors are markedly exaggerated. As well, `cross-sensitization' effects may occur wherein a stressor augments the later response to a different challenge (e.g., cocaine or immune acting agents). Sensitization effects in rodents can occur at any age, but are especially pronounced if the stressor was initially encountered in early life (first few postnatal days) or during the adolescent (juvenile) period. These sensitization effects have variously been attributed to altered sensitivity of particular receptors in brain, or altered growth factor functioning, some of which may stem from epigenetic changes. It is commonly thought that stressors at critical times necessarily have adverse effects. This may be true of strong stressors owing to reduced BDNF functioning. However, mild, tolerable stressors during early life, by increasing BDNF functioning, may enhance an animal's capacity to deal with later stressors, possibly through sensitized BDNF functioning might similarly be engendered upon later stress re-exposure, which may favor greater neurobiological and behavioral flexibility. There is yet another important element that needs to be considered in this context. Although endogenously diminished BDNF functioning, may have negative behavioral consequences, in some instances this may actually have positive effects. Adequate BDNF functioning augments synaptic plasticity, and thus an organism may gain from positive early life experiences, and be negatively affected by stressful encounters. In the absence of adequate BDNF functioning, the organism will be less likely to gain from early life positive experiences, but on the flip side, they will also be less likely to be damaged by stressful experiences. The proposed studies will assess the hypothesis that mild social stressors or fairly strong challenges encountered during the juvenile period (PND 28-30) will, respectively, enhance or disrupt later (during adulthood) cognitive flexibility in problem solving tests as well as behavior in social situations. These changes will be paralleled by neurotrophin and receptor variations. Moreover, by using genetically engineered strains of mice (conditional knockouts) we will determine whether the absence of genes for BDNF (knocked out at the juvenile period) influence later behavioral changes, as well as neurochemical variations otherwise engendered by stressors (e.g., changes of monoamines, metabolites, and receptor mRNA expression) within stress-sensitive brain regions. It is further hypothesized that the negative effects of strong juvenile stressor experiences can be reversed by subsequent positive events (essentially, the bell can be unrung), and these outcomes will be linked to neurotrophins.